Tub is a member of a small gene family, the tubby-like proteins (TULPs), with predominant expression in neurons. Mice carrying a mutation in Tub develop retinal and cochlear degeneration as well as late onset obesity with insulin resistance. During behavioral and metabolic testing, we found that homozygous C57BL/6J-Tub^tub mice have a lower respiratory quotient (RQ) than C57BL/6J controls prior to the onset of obesity, indicating that tubby homozygotes fail to activate carbohydrate metabolism and instead rely on fat metabolism for energy needs. In concordance with this, tubby mice show higher excretion of ketone bodies and accumulation of glycogen in the liver. Quantitation of liver mRNA levels shows that during the transition from light to dark period tubby mice fail to induce glucose-6-phosphate dehydrogenase (G6pdh) the rate limiting enzyme in the pentose phosphate pathway which normally supplies NADPH for de novo fatty acid synthesis and glutathione reduction. Reduced G6PDH protein levels and enzymatic activity in tubby mice lead accordingly to lower levels of NADPH and reduced glutathione (GSH), respectively. mRNA levels for the lipolytic enzymes acetyl-coA synthetase and carnitine palmitoyltransferase are increased during the dark cycle and decreased during the light period and several citric acid cycle genes are dysregulated in tubby mice. Examination of hypothalamic gene expression showed high levels of preproorexin mRNA leading to accumulation of orexin peptide in the lateral hypothalamus. We hypothesize that abnormal hypothalamic orexin expression leads to changes in liver carbohydrate metabolism, and may contribute to the moderate obesity observed in tubby mice.